Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model

Toyoda, Hiroo; Formby, Bent

doi:10.1002/(sici)1521-1878(199809)20:9<750::aid-bies8>3.0.co;2-k

Cited by 28 publications

(9 citation statements)

References 71 publications

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“…NOD mice spontaneously develop autoimmune diabetes, which shares many immunological and pathological features with human T1D (33). The T1D in these mice can be significantly accelerated and synchronized by cyclophosphamide (CY).…”

Section: Resultsmentioning

confidence: 99%

The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Ruan

Wang

Kameswaran

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

188

148

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Death of pancreatic β cells is a pathological hallmark of type 1 diabetes (T1D). However, the molecular mechanisms of β cell death and its regulation are poorly understood. Here we describe a unique regulatory pathway of β cell death that comprises microRNA-21, its target tumor suppressor PDCD4, and its upstream transcriptional activator nuclear factor-κB (NF-κB). In pancreatic β cells, c-Rel and p65 of the NF-κB family activated the mir21 gene promoter and increased miR-21 RNA levels; miR-21 in turn decreased the level of PDCD4, which is able to induce cell death through the Bax family of apoptotic proteins. Consequently, PDCD4 deficiency in pancreatic β cells renders them resistant to death, and PDCD4 deficiency in NOD or C57BL/6 mice conferred resistance to spontaneous diabetes and diabetes induced by autoimmune T cells or the β cell toxin streptozotocin (STZ). Thus, the NF-κB−microRNA-21−PDCD4 axis plays a crucial role in T1D and represents a unique therapeutic target for treating the disease.

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Section: Resultsmentioning

confidence: 99%

The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Ruan

Wang

Kameswaran

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

188

148

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“…Numerous reports [2,[19][20][21][22] have clarified that Th1 cells are intimately involved in the onset of type 1 diabetes. In this study, we generated NOD mice lacking CXCR3, which has been considered to make a major contribution to the cytotoxic functions of Th1 cells, and we anticipated that diabetes onset in these mice would be delayed or suppressed.…”

Section: Discussionmentioning

confidence: 99%

Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice

et al. 2012

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“…For example, T cell-mediated immunity differs between NOD mice and C57BL/6 mice. 30,31 T cells are thought to play a crucial role in arteriogenesis. 32 Furthermore, because NOD mice have normal plasma cholesterol levels, it is unlikely that cholesterol or its metabolites caused reduced collateral formation in NOD mice.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia Reduces Collateral Artery Growth More Dominantly Than Hyperglycemia or Insulin Resistance in Mice

Weel

Vries

Voshol

et al. 2006

ATVB

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Objective-Collateral artery development (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease, may be deregulated by vascular risk factors, eg, diabetes or hypercholesterolemia. Here, we compared the effects of either disturbed glucose metabolism or disturbed lipid metabolism on arteriogenesis. Methods and Results-Femoral artery occlusion was performed in streptozotocin(STZ)-treated mice, nonobese diabetic (NOD) mice, and insulin-resistant Ob/Ob mice on regular diet, and APOE3*Leiden mice on different hypercholesterolemic diets. Angiography and laser Doppler perfusion analysis of hindlimbs were performed postoperatively. Surprisingly, angiographic arteriogenesis was not impaired in diabetic and insulin-resistant mice. Perfusion recovery in STZ-treated and Ob/Ob mice was only decreased by 19% and 16%, respectively (PϽ0.05). Furthermore, perfusion recovery was unchanged between high-glycemic and mild-glycemic NOD mice. Angiographic arteriogenesis in APOE3*Leiden mice, however, was markedly impaired at 7 days and 14 days (PՅ0.01). Correspondingly, perfusion recovery was 41% decreased in APOE3*Leiden mice (PϽ0.05). There was an inverse correlation of perfusion recovery with plasma cholesterol (Pϭ0.02), but not with triglyceride, free fatty acid, glucose, or insulin levels. Conclusions-Hypercholesterolemia reduces arteriogenesis more dominantly than hyperglycemia or hyperinsulinemia in mice. This suggests that a disturbed lipid metabolism as observed in diabetic patients might be crucial for the impairment of collateral formation. Key Words: arteriogenesis Ⅲ cholesterol Ⅲ collateral circulation Ⅲ diabetes Ⅲ NOD mice Ⅲ peripheral vascular disease H yperlipidemia and diabetes mellitus are 2 major risk factors for coronary and peripheral arterial disease, in addition to nicotine abuse, hypertension, and other factors, by increasing the progression of atherosclerosis. 1 Moreover, collateral artery development (arteriogenesis), a vital compensatory mechanism in patients with arterial occlusive disease, 2,3 is deregulated by both hyperlipidemia 4 -8 and diabetes. 9,10 Poor arteriogenesis may influence the rate of disease progression and susceptibility for therapeutic intervention, such as direct revascularization techniques, exercise training, or experimental therapies to promote arteriogenesis. 11,12 Because both hyperlipidemia and diabetes often coexist in patients with arterial obstructive disease, it is difficult to determine which risk factor plays a predominant role in the impairment of collateral formation.Moreover, evidence is accumulating that a disturbed lipid metabolism is a crucial determinant of the development of diabetes and its complications, such as accelerated atherosclerosis. For example, disordered fat storage and mobilization, mainly involving triglyceride and free fatty acid metabolism, were implicated in the pathogenesis of insulin resistance and type 2 diabetes. [13][14][15][16][17][18] Furthermore, considerable attention has been drawn to the glycation and/...

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Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model

Cited by 28 publications

References 71 publications

The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice

Hypercholesterolemia Reduces Collateral Artery Growth More Dominantly Than Hyperglycemia or Insulin Resistance in Mice

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